This proposal responds to RFA-EB-18-003 HEAL initiative: Translational Development of Devices to Treat Pain, and aims to develop a next-generation noninvasive neuromodulation system that supports a device- based strategy for non-addictive pain treatments. Specifically, we will build an integrated magnetic resonance (MR) image-guided focused ultrasound (MRgFUS) stimulation system for targeted and high precision modulation of pain regions and circuits. Although there are several devices available on the market to treat pain, their efficacy is limited by imprecise targeting resulting from insufficient mechanistic data about the ?device-able? targets, and from lack of feedback of effects to modulate the therapy (as stated in the RFA). Reversible FUS stimulation under MRI guidance (MRgFUS) combines the dual neuromodulation capacity of low frequency focal ultrasound with simultaneous monitoring of neuromodulation in action using fMRI. MRgFUS overcomes the limitations of existing pain-treatment devices, and has great potential to improve patient outcomes through FUS and MRI technologies that enable targeting and control. Our group has developed an MRgFUS system for non-human primate (NHP) use and successfully modulated neural activity in the somatosensory cortex as observed by fMRI. Here we propose to improve and translate this early-stage technology into new non-addictive pain treatments by developing and integrating innovative FUS and MRI technologies and scaling up the NHP system to humans. We will use the nociceptive pain system of the NHP as our test model since NHP brains closely resemble the human brain in function and structure. The goals will be to overcome the substantial technological challenges required to accurately and reliably stimulate identified regions of cortex, and to navigate precisely under MR guidance to three specific pain targets (thalamic nuclei, ACC, and PAG/PVG) that are currently used in clinical pain treatments, and to subsequently monitor the responses of the nociceptive pain circuits using a functional MRI (fMRI) readout. We will focus on the challenges of targeting focused ultrasound beams safely within the head with high resolution and accuracy, of providing real-time feedback of the amplitude and distribution of the modulating sound fields at sub-thermal doses, and of rapid imaging of FUS action on the activity of pain regions and circuits based on blood oxygenation level dependent (BOLD) signatures and gold-standard microelectrode electrophysiology. We will develop engineering solutions for neuronavigation and dosimetry that are critical for the clinical deployment of FUS neuromodulation. The three partnering laboratories will address the following Aims: (Aim 1) Development of focused ultrasound technology for neuromodulation in humans. (Aim 2) Development of MRI Technology for neuromodulation. (Aim 3) Validation of MRgFUS neuromodulation of brain pain regions in NHPs. By the end of the project, we will have a fully developed and validated MRIgFUS system that is ready for pilot clinical trials in various pain management applications.